Circulatory cholesterol levels are inversely linked to mortality of patients with sepsis and critical illness

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Lily Ramsey, LLMFeb 1 2024

In a recent systematic review and meta-analysis published in eBioMedicine, researchers examined the association between biomarkers of cholesterol homeostasis and mortality in critically ill patients.

They found that systemic cholesterol levels, including total cholesterol (TC), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) on admission to critical care, are inversely associated with mortality.

Study: Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies. Image Credit: SurfsUp/Shutterstock.com

Background

Evidence suggests that deviations from the normal equilibrium range of TC, HDL-C, and LDL-C are linked to chronic inflammatory conditions.

Cholesterol metabolism is regulated by interferon cytokine responses and is known to play a central role in immunity and host defense. HDL-C neutralizes and clears toxins from infections, influencing immune effector functions.

Previous reports have revealed an inverse correlation between inflammatory cytokines and serum cholesterol levels in sepsis, alongside consistent associations between low cholesterol levels and deaths in critically ill adults, particularly in sepsis.

While HDL-based infusion has been explored for sepsis treatment, causative relationships between serum cholesterol and clinical outcomes require further investigation.

The present systematic review and meta-analysis across mixed populations admitted to the intensive care unit (ICU) aimed to evaluate the relationship between LDL-C, HDL-C, TC, and mortality in critical illness, providing insights for future research in diagnostics and therapeutics.

About the study

In the present study, the databases Embase, Ovid Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Web of Science, PubMed, and SCOPUS were systematically searched from their inception until October 3, 2023.

Two reviewers independently screened the articles based on specific inclusion and exclusion criteria.

The included studies were prospective, involved adult subjects (≥16 years old) in intensive care, recorded in-hospital, ICU, or short-term mortality (<30 days), measured serum TC and/or HDL-C and/or LDL-C on the day of ICU admission, and assessed the association between serum cholesterol and hospital mortality.

The review included 29 prospective observational cohort studies (conducted between 2000 and 2022) involving 3,003 adult participants of both genders. The studies assessed serum TC, HDL-C, and LDL-C levels on the day of admission to critical care.

Of these, 24 studies with 2542 participants were employed in the quantitative meta-analysis, with 13 studies focusing on patients with sepsis on ICU admission.

The remaining studies covered various critical illnesses, including acute kidney injury, acute liver failure, acute heart failure, severe acute pancreatitis, multiple organ failure, systemic inflammatory response syndrome (SIRS), surgical ICU admissions, general ICU cohorts, severe community-acquired pneumonia, and coronavirus disease 2019 (COVID-19) pneumonia.

The quality of the cohort studies was evaluated using a modified Newcastle–Ottawa Scale (NOS), and potential confounders were identified. Statistical analysis involved the use of weighted mean differences, a random effects model, I2 statistic, Egger's regression test, and meta-regression.

Results and discussion

Study quality varied between 5 and 7 (out of 9), with potential bias stemming from poor comparability between survivor and non-survivor cohorts due to undetected and unadjusted confounding factors across all studies.

TC

Participants who died had significantly lower serum TC on the first day of ICU admission compared to survivors, with a pooled mean difference of -21.86 mg/dL across 22 studies with high heterogeneity.

Adjusting for age and proportion of males did not alter the results, and sensitivity analysis aligned with the main results. Meta-regression suggested the proportion of males as a significant covariate.

HDL-C

Patients who died exhibited significantly lower serum HDL-C on the first day of ICU admission, with a pooled mean difference of -7.06 mg/dL across 17 studies showing moderate heterogeneity. Adjustment for the proportion of males and mean age did not alter the overall trend, and no significant publication bias was observed.

LDL-C

Patients who died exhibited significantly lower serum LDL-C on the first day of ICU admission, with a pooled mean difference of -8.79 mg/dL across 16 studies with moderate heterogeneity.

Adjustment for the proportion of male and mean age reduced heterogeneity, and no significant publication bias was observed. Meta-regression identified the proportion of males as a significant covariate, with the mean difference increasing with a higher proportion of males in a study.

Limitations of the study include challenges in fully controlling patient characteristics affecting both mortality and serum cholesterol, adjusting for confounders at the individual level, and variability in accounting for statin use among the studies.

Conclusion

In conclusion, these findings support the prognostic value of decreased HDL-C levels in sepsis and critical illness, suggesting the potential clinical utility of subclass-specific HDL biomarkers for early sepsis detection.

Future investigations could explore cholesterol esters as implementable HDL-associated biomarkers and precisely define subclasses to establish reference ranges indicative of severe illness.